A variety of medical techniques suitable for imaging biological tissues and organs are known. These include traditional x-rays, ultra-sound, magnetic resonance imaging, and computerized tomography.
A variety of dyes useful for medical imaging have been described, including radio opaque dyes, fluorescent dyes, and colorimetric dyes (see e.g., U.S. Pat. Nos. 5,699,798; 5,279,298; 6,351,663). Imaging techniques and systems using fluorescent dyes have been described for the heart and eye (see, e.g., U.S. Pat. No. 5,279,298). Some dyes can serve both an imaging function and a therapeutic function (see, e.g. U.S. Pat. No. 6,840,933). Some specific neuronal imaging agents have been used to visualize tissue in the central nervous system. Tracer uptake and transport has been demonstrated in different studies using various routes of administration including antegrade, retrograde and combined routes (Jones et al. 1978, Annu Rev Neurosci., 1:215; Rosina A., 1982, Neurosci Lett. 33(3):217; Illing R B, et al., 1985, Neuroscience 14(2):455; Sloniewski P, et al., 1985, Neurosci Lett. 60(2):189; and Schmued et al., 1986, Brain Res. 377(1):147). After appropriate time for endo/pinocytosis, perineural lymphatic and axonal transport, which generally measures 0.5-2 mm per hour, tracers were visually detected using ultraviolet or visible light (Bentivoglio et al., 1980, Neurosci Lett. 18(1):19; Minciacchi D et al., 1991, J Neurosci Methods. 38(2-3):183). Tracers such as Indocyanine Green, Fast Blue, and Fluorogold, have been used in mammals without evidence of neuronal toxicity several months after the treatment (Thielert et al., 1993, J Comp Neurol. 337(1):113; Yeterian et al., 1994, Exp Brain Res. 99(3):383; vogt Weisenhorn et al., 1995, J Comp Neurol. 362(2):233). Marangos et al. labeled the auditory nerve using Fluorogold and Fast Blue in rats and monkeys by suctioning out perilymph and filling the cochlea with neuronal tracers to identify the nerve and cochlear brain stem nucleus for the positioning of electrodes for an auditory neuroprosthesis (Marangos N, et al., 2001, Hear Res. 162(1-2):48).
According to the American Cancer Society, only some 1,500 cases are diagnosed a year in the U.S., accounting for only 0.2% of cancers in men in the U.S. Although penile cancer is relatively uncommon among American and European men, it is much more common in Africa and South America, where it accounts for 10% of all male cancers. While definitive causes of penile cancer are not known, there are some known risk factors. One such risk factor is infection with human papillomavirus. In a report available on-line as of this writing, Senba et al., J Med Virol. 2006, 78(10):1341-6, reported the detection of human papillomavirus DNA in 80% of 65 samples of penile cancer from Thai men, with HPV-18 being the most prevalent. Another, in uncircumcised males, is the buildup of secretions under the foreskin.
According to the American Cancer Society, some 95% of penile cancers are squamous cell carcinomas and usually develop on the foreskin (if the male is uncircumcised) or the glans. Typically, the patient presents with a rash, bumps, ulcer or discharge, and the cancer is diagnosed by microscopic examination of biopsied tissue. Lymph node metastasis is a crucial prognostic factor in penile cancer. About 50% of patients with palpable lymph nodes will have metastases, and about 20% of patients without enlarged lymph nodes will have lymphatic spread (Hardner, G J, J Urol, 108:428ff (1972); Kossow, J H, Urology, 2:169ff (1973); McDougal, W S, J Urol 136:38ff (1986)). Successful sentinel lymph node dissection (SLND) is predicated on precise detection of the lymphatic drainage into sentinel nodes. According to the National Cancer Institute, when diagnosed early (stage 0, stage I, and stage II), penile cancer is highly curable, but curability decreases sharply for stage III and stage IV. Criteria for staging penile cancer are known in the art, and set forth at, e.g., Penis: American Joint Committee on Cancer, AJCC Cancer Staging Manual, 6th Ed., Springer, NY N.Y., 2002, pp. 302-8.
Unfortunately, there is significant anatomical variation in penile lymph node drainage as well as in sentinel lymph node position. In multiple cases, current dye or radionuclide lymphatic tracing methods result in identification of sentinel and some of the metastatic lymph nodes (Cabanas, R M, Urol Clin N Am 19:267ff (1992); Lynch, D F, Jr: AUA update series, 16:256 (1997)). Nevertheless these procedures are difficult, time-consuming, expensive and have low sensitivity, especially when used with methylene blue. If sentinel nodes are found without metastases this would obviate unnecessary removal of noninvolved nodes as seen in 90-95% of superficial lesions, 50-60% of T2 lesions, and 10-20% of T2b and T3 lesions (Horenblas et al., J Urol 155:1239-1243 (1994)). The presence of metastases will be followed by complete lymph node dissection. Current practice is to remove all inguinal or ilioinguinal lymph nodes in penile cancer surgeries, resulting in significant morbidity in more than 30% of the patients. Multiple methods, such as the use of radioactive tracers, have been used in the hope of improving the detection of sentinel nodes, see, e.g., Brennhovd et al., Sentinel node procedure in low-stage/low-grade penile carcinomas, Scand J Urol Nephrol. 2006; 40(3):204-7, but no method has yet emerged as a standard.
Accordingly, a need exists for improved methods of locating sentinel lymph nodes for persons with penile cancer. The present invention fills these and other needs.